Abstract

PURPOSE OF THE REVIEW: Review tests available for detection of Clostridium difficile (C. Diff) induced disease, including when such tests should be done in children and how they should be interpreted.

RECENT FINDINGS: Multiple tests are available for detecting disease due to C. diff. These include colonoscopy and stool analysis. Colonoscopy with biopsy is the most sensitive test for detecting the presence of colitis. The toxins produced by the C. diff. (toxin A, toxin B, and binary toxin) are the agents that cause injury and disease. Only toxin producing C. diff. Strains will cause disease. Binary toxin by itself is not thought to produce disease. Binary toxin causes disease in humans when present with toxin A and B producing bacteria, and has been implicated with fulminant life threatening disease. Stool analyses vary in sensitivity and specificity depending on the assay used. The presence of toxin producing strains of C diff. in the stool does not equate with disease. The presence of a toxin-producing bacteria or toxins (A or B) only equates with disease if diarrhea or a diseased colon (toxic megacolon, ileus, and sepsis) is present. Nucleic acid amplification testing (NAAT), when used in the stool from patients with diarrhea, appears to be the most efficient study to detect the gene that encodes for toxin A and B and thus to diagnose C. diff.-induced disease. Infants have a high carriage rate of C. diff. and are believed not to develop disease from it or its toxins. Infants should not be tested for C. difficile. The NAAT is most specific when done on patients with diarrhea with liquid stools. Testing for C. difficile should only be done on patients with diarrhea. One can assume that a patient who has no diarrhea and is not ill does not have C. diff.-induced disease. Treatment should be limited to patients with diarrhea who test positive for C. diff. toxin (A or B) or toxin-producing bacteria. Direct testing for binary toxin is not commercially available. Binary toxin is only thought to cause disease in humans when C. diff. toxin (A and B)-producing bacteria are present.

McConnie R, et al. Curr Gastroenterol Rep. 2017.

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Dutch study finds incidence of pediatric C diff stable

A study by Dutch researchers (Oct 21, 2016) finds that the incidence of pediatric Clostridium difficile infection (CDI) has been stable over the previous 6 years.

The surveillance study, published in Clinical Infectious Diseases, included all CDIs reported from May 2009 to May 2015 by 26 Dutch hospitals participating in a national sentinel surveillance study. Infected children were 2 and older.Investigators distinguished between healthcare-onset CDI (in which symptoms began in a hospital or long-term care facility) and community-onset CDI (when symptoms began at home).

Overall, 4,691 CDIs were included in the study, with a total of 135 pediatric CDIs (3%) being reported at 17 hospitals. The investigators did not observe an increase in the monthly number of reported pediatric CDIs during the study period. The median age of the children with CDI was 10 years.

Of the 135 pediatric CDI cases, 55% were community-onset, and 31% met the criteria for severe CDI. Although severe CDI was more likely to occur in children, it resulted in fewer complications than adult CDI. In contrast to adults, there was no CDI-related mortality. Pediatric CDI cases were more likely to occur in university hospitals than non-university hospitals.

The investigators also found that, of the 36 C difficile PCR ribotypes identified, ribotype 265 was most prevalent in children (15%) but rarely found in adults.

The authors note that the findings are in contrast to several studies in recent years that have shown an increase in the incidence of pediatric CDI in community settings and hospitals in the United States.Oct 19 Clin Infect Disabstract

A small pilot study featuring 15 pediatric patients found that 14 out of 15 with recurringC. difficile infections reported no additional episodes more than 3 months following the procedure, reported Aneeq Malik, BS, of Morehouse School of Medicine in Atlanta, and colleagues. They presented their results at the Pediatric Academic Societies (PAS) annual meeting.

Overall, 15 children underwent the procedure — seven male and eight female, with a mean age of 7.9 years, with at least three episodes of C. difficile within a 3-month period. The patients ranged from 21 months to 18 years, and had an average of 5.7 diarrheal stools per day, as well as an average of 3.3 courses of antibiotics within a 12-month period. Seven also had ulcerative colitis, while two apiece had Crohn’s disease and GERD.

Following a stool transplant from a pre-screened stool bank, patients were followed up via phone at 24 hours and 1 week after the procedure and were instructed to see their GI doctor at 1 and 3 months afterwards. Three patients were hospitalized a month following the procedure for diarrhea, dehydration and rCDI. However, only one patient was actually found to have clinical symptoms of C. difficile plus a positive stool test.

Limitations to the study included the size of the sample, as well as the fact that clinical symptoms were based on self-report and that several of their patients had underlying GI conditions. Co-author Lilly Immergluck, MD, also of Morehouse School of Medicine, said at the presentation that she considered that a strength of the study — that the success rate of the procedure was high, despite the patients’ other conditions.

Brandt said that despite limitations, he still characterized the procedure as exciting and said the evaluation of the microbiome will be very important for the future of this research.

“I think in the future we probably will not be using stool – we’ll be using some product derived from stool – because we don’t really know what the protecting organism is,” he said.

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In this episode Tex Kissoon, MD,a well-known physician from Canada, provided us with the insight into the global phenomenon of Sepsis. Sepsis affects more than 30 million lives per year yet it is almost unknown to the general public and is quite often misdiagnosed by medical professionals worldwide. The reasons of why that is with the “why” Sepsis is so deadly, and what you can do to increase Sepsis awareness– were discussed in 60 minutes. Dr. Kissoon was joined by Ray Schachter, a Sepsis survivor who now dedicates all of his available time raising awareness of Sepsis worldwide. Both guests are members of the Global Sepsis Alliance (GSA), which has established World Sepsis Day on September 13thevery year to raise awareness for Sepsis worldwide.

About Our Guests:

Dr. Niranjan “Tex” Kissoon, MD

Dr. Kissoon is the Past President of the World Federation of Pediatric Critical and Intensive Care Societies, Vice-President, Medical Affairs at BC Children’s Hospital and Professor, Pediatric and Surgery (Emergency Medicine) Department of Pediatrics at the University of British Columbia in Vancouver, BC as well as he holds the University of British Columbia BC Children’s Hospital (UBC BCCH) Endowed Chair in Acute and Critical Care for Global Child Health. Dr. Kissoon is the vice chair of the Global Sepsis Alliance, co-chair of World Sepsis Day and the International Pediatric Sepsis Initiative.). He has been involved in both advocacy and in promoting Canada-wide involvement in World Sepsis Day as part of a global initiative. He is also involved in promoting sepsis guidelines such that appropriate treatments are given even in areas where there are limited resources.

Dr. Kissoon was awarded a Distinguished Career Award by the American Academy of Pediatrics in 2013 for his contribution to the society and discipline as well as the prestigious Society of Critical Care Medicine’s (SCCM) Master of Critical Care Medicine award in 2015 in recognition of his tireless efforts and achievements as a prominent and distinguished leader of national and international stature. He was also awarded the BNS Walia PGIMER Golden Jubilee Oration 2015 Award for major contribution to Pediatrics in India from the Postgraduate Institute Medical Education and Research.

A Direct Quote From Our Guest and Sepsis Survivor; Ray Schachter:

“I miraculously survived acute Sepsis in 1996 due to extensive medical intervention and have experienced the immediate and long-term consequences on me and my family. I am the Chair of the Global Sepsis Alliance (GSA) Task Force whose goal is to have the UN mandate Sepsis as a World Health Day. Working with these very accomplished and committed people from GSA, many of whom are on the GSA Executive or Ambassadors, on this important project is a very special opportunity.”

About The Global Sepsis Alliance (GSA):
Sepsis is one of the most underestimated health risks. It affects more than 30 million people worldwide each year; for 6 to 8 million of them with a fatal outcome. Surviving patients often suffer for years from late complications.
This is all the more disturbing as sepsis incidence could be considerably reduced by some simple preventive measures such as vaccination and improved adherence to hygiene standards, early recognition and optimized treatment. The main danger of sepsis results from a lack of knowledge about it.
The founding members of the Global Sepsis Alliance (GSA) have recognized the need to elevate public, philanthropic and governmental awareness and understanding of sepsis and to accelerate collaboration among researchers, clinicians, associated working groups and those dedicated to supporting them. For this reason, they initiated the Global Sepsis Alliance in 2010. Together with supporting organizations from across the globe, we are united in one common goal:

The GSA wants to ensure that:

The incidence of sepsis decreases globally by implementation of strategies to prevent sepsis.

Sepsis survival increases for children (including neonates) and adults in all countries through the promotion and adoption of early recognition systems and standardized emergency treatment

Public and professional understanding and awareness of sepsis improve

Access to appropriate rehabilitation services improve for all patients worldwide

The measurement of the global burden of sepsis and the impact of sepsis control and management interventions improve significantly

The GSA Current priorities:

Acknowledgement of a resolution on sepsis including official designation of World Sepsis Day (WSD) as one of the World Health Days by the World Health Assembly.

Recognition of sepsis in the Global Burden of Disease Report

Increase of public awareness and implementation of quality improvement initiatives

Cubist Pharmaceuticals, Inc. today announced it will present new data from a phase 1 safety and pharmacokinetic study of fidaxomicin in children with Clostridium difficile-associated diarrhea (CDAD) at IDWeek 2014, being held October 8-12 in Philadelphia.

These new data will be featured as a late-breaking oral presentation (LB-8, session #186) Saturday, October 11, 2014, at 10:30 a.m. EDT, given by Pam Sears, Vice President, Clinical Sciences, Cubist.

The presentation will provide early insight into the safety, pharmacokinetic profile and efficacy of fidaxomicin in children who have CDAD.

“Children, especially those who have serious underlying medical conditions, are susceptible to Clostridium difficile-associated diarrhea, which can be very serious,” said Steven Gilman, Ph.D., Executive Vice President of Research and Development and Chief Scientific Officer of Cubist Pharmaceuticals. “These first data of fidaxomicin in children are important because they offer the first insights into a patient population that is typically excluded from Phase 3 clinical trials.”

At least one adverse event was reported in 73.7% of patients. The majority of adverse events were categorized as mild (44.7%) or moderate (21.1%). Nine severe adverse events were observed during the course of the study and were not considered related to fidaxomicin. The pharmacokinetic profile seen in this study is similar to the profile shown in an adult population. Although not powered to assess efficacy, the clinical response observed in the study was 92.1%. The infections recurred in 28.6% of patients, all but one of whom had a history of recurrent CDAD.

“This study supports the further evaluation of fidaxomicin in children with C. difficile-associated diarrhea,” said Pam Sears. “As CDAD is most often observed in adults, there is much less information known about the pediatric presentation of the disease, and we are excited to present the results of our first study on the treatment of CDAD in children. We hope the results presented at IDWeek 2014 encourage ongoing dialogue and exchange on this important topic.”

In addition to this study, Cubist’s other presentations at IDWeek 2014 will feature the company’s portfolio of antibiotics for serious infections caused by multidrug-resistant bacteria. Data highlighted will offer insights into Cubist’s commitment to identifying treatments for drug-resistant Gram-positive and Gram-negative bacteria that cause serious infections.

Fidaxomicin is not currently approved for use in pediatric patients. Fidaxomicin is marketed in the U.S. as DIFICID® for the treatment of adult CDAD.

Indication and Important Safety Information

DIFICD Indication and Usage

DIFICID® (fidaxomicin) is indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD)

To reduce the development of drug-resistant bacteria, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile

DIFICD Important Safety Information

DIFICID should not be used for systemic infections.

Acute hypersensitivity reactions (angioedema, dyspnea, pruritus, and rash) have been reported. In the event of a severe reaction, discontinue DIFICID

Development of drug-resistant bacteria: Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria

Cubist has a growing commitment to global public health through its leadership in the discovery, development and commercialization of novel antibiotics to treat serious and potentially life-threatening infections caused by a broad range of increasingly drug-resistant bacteria. The Company hopes to deliver at least four new antibiotics in support of the Infectious Diseases Society of America (IDSA) goal of 10 new antibiotics by 2020. Cubist expects to invest approximately $400M USD in 2014 on antibacterial R&D and approximately 75% of its employee base is focused on the research, development, commercialization and support of antibiotics.

About Cubist

Cubist Pharmaceuticals, Inc. is a global biopharmaceutical company focused on the research, development, and commercialization of pharmaceutical products that address significant unmet medical needs in the acute care environment. Cubist is headquartered in Lexington, Massachusetts, with a central international office located in Zurich, Switzerland. Additional information can be found at Cubist’s web site at www.cubist.com. Also, connect with Cubist on Twitter @cubistbiopharma and @cubistcareers, LinkedIn, or YouTube.

About IDWeek 2014TM

IDWeek 2014TM is an annual meeting of the Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA) and the Pediatric Infectious Diseases Society (PIDS). With the theme “Advancing Science, Improving Care,” IDWeek features the latest science and bench-to-bedside approaches in prevention, diagnosis, treatment, and epidemiology of infectious diseases, including HIV, across the lifespan. IDWeek 2014 takes place October 8-12 at the Pennsylvania Convention Center in Philadelphia, Pennsylvania. The full name of the meeting is IDWeek 2014TM.For more information, visit www.idweek.org.

Forward Looking Statements

This press release contains forward-looking statements. Any statements contained herein which do not describe historical facts, including but not limited to, statements regarding: our intention to present data at IDWeek 2014 from a phase 1 study of fidaxomicin in children with CDAD, including our view that this study supports further evaluation of fidaxomicin in children with CDAD; our intention to present at IDWeek 2014 regarding our other antibiotics; our commitment to identifying treatments for drug-resistant bacteria that cause serious infections, including our commitment to global public health in this area; the level of our financial and personnel commitments towards antibiotic research, development and commercialization; our aspirations to achieve a portion of the IDSA goal of 10 new antibiotics by 2020; and the therapeutic potential of our products, are forward-looking statements which involve risks and uncertainties that could cause actual results to differ materially from those discussed in such forward-looking statements. Such risks and uncertainties include, among others: the fact that drug development involves a high degree of risk and a high rate of failure and success in early stage clinical trials does not mean that later stage trials will be successful; regulatory developments in the U.S. and other countries; the strength of, and our ability to successfully obtain, maintain and enforce intellectual property protecting our products; the fact that drug discovery and development is complex, time consuming, expensive and fraught with a high risk of failure; we are dependent on our ability to successfully work with, and the performance of, our third party clinical research organizations that we significantly rely on to help us conduct clinical trials; the timing and feasibility of any new clinical trials is dependent on our ability to successfully work with regulatory authorities, including the FDA on the design of the trials, among other things; technical difficulties or excessive costs relating to the manufacture or supply of our products, including our dependence on and the performance of our third party contract manufacturers that manufacture and supply our products on our behalf and those additional factors discussed in our most recent annual report on Form 10-K and subsequent quarterly reports on Form 10-Q filed with the Securities and Exchange Commission and available at http://www.sec.gov

We caution investors not to place considerable reliance on the forward-looking statements contained in this press release. These forward-looking statements speak only as of the date of this press release, and we undertake no obligation to update or revise any of these statements.

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